It is with deep sadness that we report the passing of our friend, mentor, and colleague, Leland W.K. Chung, Ph.D., Cedars-Sinai Distinguished Scientist, Departments of Medicine and Surgery on May 10, 2021, of renal cancer. His global reputation as an innovative researcher, team building, warmth and humility are universally appreciated by all who had the opportunity to interact with him. In his 80 years of life and scientific career spanning six decades, Leland made significant contributions to understanding how hormones act on male accessory organs to induce normal development, maintain differentiated phenotypes, and the critical role of heterotypic cellular interactions in neoplastic transformation, cancer progression and tumor metastasis. The disease models developed by his laboratory have been used widely to study specific prostatic cancer (PCa) disease processes and evaluate drug and gene therapies. His translational research collaborations have helped bring innovative technologies and treatments to clinical oncology trials1. Dr. Chung published over 250 peer-reviewed manuscripts, book chapters and invited review articles.
Leland Chung was born on Sept. 30, 1940, during a wartime air raid and pursued youthful interests in botany and athletic competition as a sprinter. After completing undergraduate studies at the National Taiwan University, Leland arrived in the US to pursue his graduate studies at the University of Oregon Health Sciences Center Department of Pharmacology, earning his Ph.D. in 1969. The subject of his doctoral dissertation was biochemical characterization of corticosteroid-induced involution of the thymus2. His postdoctoral fellowship at the Department of Experimental Therapeutics at the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine from 1969-1972 influenced him profoundly in two ways.
- Leland’s laboratory studies into androgen regulation of rodent accessory sex organ growth and regression are classic publications in the scientific literature. This work laid the cornerstone for his subsequent research career efforts to elucidate the etiology, progression, and treatment of prostatic cancer3.
- Leland’s association with his post-doctoral mentor, Dr. Donald S. Coffey, reinforced the value of servant leadership to students, post-doctoral fellows, laboratory staff, and colleagues to building and overseeing successful and productive research teams. Leland followed Dr. Coffey’s example by giving credit to others, living with integrity and curiosity, maintaining intellectual rigor, open-mindedness, and speaking out against unfounded dogma and injustice. Leland transmitted Dr. Coffey’s practical application of critical thinking passed to trainees with his advice: “let your data speak to you and do not assume what cannot be proven experimentally.”
Leland considered his legacy to be a teacher in a line of mentors. Leland, much like Helen of Troy, launched a thousand researchers around the globe with his wonderful and beautiful mind. He lived the ethic that giving to others leads to a synergistic cycle of personal satisfaction and happiness. He also emphasized to his colleagues, students, and fellows, the value of scientific collaborations to make meaningful contributions to understanding and treating diseases.
Leland’s lifelong collaborator and life partner was his wife, Dr. Haiyen Zhau. In addition to her intellectual input and research efforts, Haiyen was instrumental in maintaining the work-life balance in their family, enabling the raising and nurturing their two daughters, Shunney and Leia. At McGill University, Haiyen and Leland discovered and characterized the role of androgens in neonatal imprinting and adult maintenance of cytochrome P-450 enzymatic activity responsible for the metabolism of testosterone5. These imprinting studies raised fundamental questions as to the roles played by the tissue microenvironment in maintaining hormone sensitivity, tissue phenotype and function in developmental, normal and neoplastic states. At the University of Colorado, Boulder, Leland pursued these concepts and questions in collaboration with Dr. Gerald R. Cunha, a developmental biologist at the Medical School in Denver. The complimentary expertise, philosophies, and temperaments of these two investigators provided an exciting and productive research environment where postdoctoral fellows cross-trained and conducted experiments jointly, team members routinely discussed science outside the lab, and reports were published that are considered to be classics in the field of hormonal regulation of prostatic growth and function6,7.
Recognizing the potential of contact and collaboration with clinical investigators, Leland accepted the position of Director of the Urology Research Laboratory at The University of Texas (UT) M.D. Anderson Cancer Center (MDACC). The translational research pursued at by Leland and collaborators at MDACC and UT Houston applied techniques and concepts of heterotypic cellular interactions to understanding the propensity of prostatic cancer to metastasize to bone. In a radical departure from the widely used contemporary approach employing oncogene-induced epithelial transfection, he developed a model of human prostatic cancer progression and bone metastasis driven by stroma-driven epigenetic signalling8-10. This unique model and its derivative cell lines have proven useful to study cell signalling and bone metastasis mechanisms, and to evaluate preclinically, a variety of potential drug and gene therapies11,12.
Leland subsequently founded the Molecular Urology and Therapeutics Program at the University of Virginia Medical Center, Charlottesville, where his team identified and characterized androgen-independent, bone metastatic, and lethal human prostatic cancer geno- and phenotypes. This laboratory effort provided the rationale, models, and supporting preclinical data to evaluate potential viral vector-based gene therapies promoters13,14. Ultimately, a clinical trial was conducted successfully targeting prostatic cancer lymph node and bone metastases using adenoviral vector cytotoxic gene therapy under the control of tissue-specific and tumor-restricted promoters15. This was the first time ever that a live adenovirus (AD-OC-TK) was directly injected into a lymph nodes, bone metastases and local recurrence of prostate cancer.
Based upon their laboratory findings and previous publications, Leland and colleagues hypothesized that osseous metastatic prostate cancer cells express an osteomimetic phenotype to metastasize, survive and proliferate in skeletal sites. Their model invoked reciprocal interactions between prostatic cancer and bone stromal growth factors to initiate bone tropism and differentiation to produce the characteristic human osteoblastic phenotype16. Their laboratory experiments identified specific prostate cancer and bone stromal cell proteins expressed in the experimentally induced osseous lesions. Expression of these common proteins were proposed as targets for selective gene therapies driven by tissue-specific and tumor-restricted promoters for the safe delivery and expression of therapeutic genes in experimental models of prostate cancer metastasis.
At Emory University Dept. of Urology, Leland and collaborators continued development of in vitro heterotypic cell co-culture systems17 and employed highly sensitive imaging techniques to evaluate heterotypic cellular interactions in primary and bone metastatic prostatic cancer tumor microenvironments. Their findings in tumor-bearing mice revealed in real-time, dynamic processes involved in progression and response to novel experimental therapies18,19. This work characterized interactions between cancer and non-cancer cells and demonstrated that subpopulations of cancer cells recruit bystander cancer cells to participate in tumor metastasis.
As director of the Urologic Oncology Research Program at Cedars-Sinai Cancer Center, Leland’s lab advanced molecular imaging techniques, developed additional three-dimensional cellular coculture models, and evaluated near-infrared fluorescent dyes (NIRF) for the detection and imaging of prostatic cancer19. These imaging findings were extended to potential therapeutic applications in preclinical studies demonstrating treatment with conjugate agents comprised of 1) NIRF dye (heptamethine carbocyanine)-Cytoreductive (docetaxel), 2) NIRF dye-Iron oxide nanoparticle (Ferumoxytol®) and 3) NIRF dye-Tyrosine kinase inhibitor (cabozantinib) produced PCa tumor shrinkage and reduced tumor spread 20. These proof-of-concept experiments validated the concept that NIRF dye-drug conjugates may provide a platform of selective post-operative nanotheranostic agents to treat PCa and other intractable malignancies.
Leland Chung committed his intellect and gifts of scientific leadership, forward thinking, and integrity to curing cancer. His commitment to research, humility, and respect for others leaves us an inspirational legacy and personal example to follow. We share the sentiment of his many post-doctoral fellows and consider ourselves fortunate to have spent time with this inspirational man.
- Chung LWK. Better to give than receive: My exciting journey in science. Cancer Biology & Therapy. 2005;4(3):348-52. doi: 10.4161/cbt.4.3.1569.
- Chung LWK, Gabourel JD. Adrenal steroid release by vinblastine sulfate and its contribution to vinblastine sulfate effects on rat thymus. Biochemical Pharmacology. 1971;20(8):1749-56. doi: https://doi.org/10.1016/0006-2952(71)90372-8.
- Chung LWK, Coffey DS. Biochemical characterization of prostatic nuclei. I. Androgen-induced changes in nuclear proteins(0006-3002 (Print)).
- Chung LWK, Chao H. Neonatal imprinting and hepatic cytochrome P-450. I. Comparison of testosterone hydroxylation in a reconstituted system between neonatally imprinted and nonimprinted rats. Mol Pharmacol. 1980;18(3):543-9. Epub 1980/11/01. PubMed PMID: 6780782.
- Cunha GR, Chung LWK. Stromal-epithelial interactions--I. Induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J Steroid Biochem. 1981;14(12):1317-24. Epub 1981/12/01. doi: 10.1016/0022-4731(81)90338-1. PubMed PMID: 6460136.
- Chung LWK, Cunha GR Stromal-epithelial interactions: II. Regulation of prostatic growth by embryonic urogenital sinus mesenchyme(0270-4137 (Print)).
- Chung LWK, Chang SF, Bell C, Zhau HE, Ro JY, von Eschenbach AC. Co-inoculation of tumorigenic rat prostate mesenchymal cells with non-tumorigenic epithelial cells results in the development of carcinosarcoma in syngeneic and athymic animals(0020-7136 (Print)).
- Camps JL, Chang SF, Hsu TC, Freeman MR, Hong SJ, Zhau HE, Zhau He, von Eschenbach AC, Chung LWK. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo(0027-8424 (Print)).
- Gleave M, Hsieh JT, Gao CA, von Eschenbach AC, Chung LWK. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts(0008-5472 (Print)).
- Thalmann GN, Anezinis PF, Chang SM, Zhau HE, Kim EE, Hopwood VL, Pathak S, von Eschenbach AC, Chung LWK. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer(0008-5472 (Print)).
- Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LW. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells(0020-7136 (Print)).
- Ko SC, Cheon J, Kao C, Gotoh A, Shirakawa T, Sikes RA, Karsenty G, Chung LW. Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models. Cancer Res. 1996;56(20):4614-9. Epub 1996/10/15. PubMed PMID: 8840973.
- Gotoh A, Ko SC, Shirakawa T, Cheon J, Kao C, Miyamoto T, Gardner TA, Ho LJ, Cleutjens CB, Trapman J, Graham FL, Chung LW. Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer(0022-5347 (Print)).
- Kubo H, Gardner TA, Wada Y, Koeneman KS, Gotoh A, Yang L, Kao C, Lim SD, Amin MB, Yang H, Black ME, Matsubara S, Nakagawa M, Gillenwater JY, Zhau HE, Chung LW. Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. Hum Gene Ther. 2003;14(3):227-41. Epub 2003/03/18. doi: 10.1089/10430340360535788. PubMed PMID: 12639303.
- Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. 1999;39(4):246-61. Epub 1999/05/27. doi: 10.1002/(sici)1097-0045(19990601)39:4<246::aid-pros5>3.0.co;2-u. PubMed PMID: 10344214.
- Wang R, Xu J, Juliette L, Castilleja A, Love J, Sung SY, Zhau HE, Goodwin TJ, Chung LW. Three-dimensional co-culture models to study prostate cancer growth, progression, and metastasis to bone. Semin Cancer Biol. 2005;15(5):353-64. Epub 2005/06/29. doi: 10.1016/j.semcancer.2005.05.005. PubMed PMID: 15982899.
- Gao X, Cui Y, Levenson RM, Chung LW, Nie S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol. 2004;22(8):969-76. Epub 2004/07/20. doi: 10.1038/nbt994. PubMed PMID: 15258594.
- Chung LW, Baseman A, Assikis V, Zhau HE. Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J Urol. 2005;173(1):10-20. Epub 2004/12/14. doi: 10.1097/01.ju.0000141582.15218.10. PubMed PMID: 15592017.
- Teh J, Tripathi M, Reichel D, Sagong B, Montoya R, Zhang Y, Wagner S, Saouaf R, Chung LWK, Perez JM. Intraoperative assessment and postsurgical treatment of prostate cancer tumors using tumor-targeted nanoprobes. Nanotheranostics. 2021;5(1):57-72. doi: 10.7150/ntno.50095. PubMed PMID: 33391975.
Blake Lee Neubauer, PhD
Member and CO-Founder,
Teichos Laboratories. LLC